Summary
Background
Statins have favourable effects on lipid profiles, decrease total mortality and have many pleiotropic effects.
Aims
To determine and compare the pleiotropic effects of simvastatin and ezetimibe in dyslipidaemic patients.
Methods
Forty-four patients (20 postmenopausal women) with low-density lipoprotein cholesterol >130 mg/dL (or >100 mg/dL in patients with coronary artery disease or its equivalent) were treated with simvastatin 10 mg daily ( n = 21) or ezetimibe 10 mg daily ( n = 23). In blood samples taken before and three months after treatment, we measured the concentration of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A, apolipoprotein B, lipoprotein(a), homocysteine, tissue factor, von Willebrand’s factor and C-reactive protein.
Results
Baseline lipid profiles and haematological variables were similar in both groups. Simvastatin and ezetimibe decreased the concentrations of total cholesterol (262 to 189 mg/dL, p < 0.001, and 268 to 220 mg/dL, p = 0.001, respectively), low-density lipoprotein cholesterol (177 to 114 mg/dL, p < 0.001 and 196 to 146 mg/dL, p < 0.001, respectively) and C-reactive protein (1.2 to 0.3 mg/dL, p = 0.001 and 2.8 to 0.8 mg/dL, p = 0.005, respectively). Simvastatin also reduced the concentration of apolipoprotein B (125 to 93 mg/dL, p < 0.001).
Conclusion
Both drugs improved lipid profiles and C-reactive protein concentration. However, no influence was found on tissue factor or von Willebrand’s factor. Our results suggest that C-reactive protein lowering may occur in conjunction with low-density-lipoprotein cholesterol lowering and not through a specific statin pleiotropic anti-inflammatory effect.
Résumé
Contexte
Les statines ont un effet favorable sur le profil lipidémique, diminuent la mortalité totale et présentent aussi plusieurs actions pléiotropiques. Le but de cette étude était de déterminer et comparer les effets pléiotropiques de simvastatin et d’ezetimibe aux malades dyslipidémiques.
Méthodes
Quarante-quatre malades (20 femmes postmenopausales) avec basse densité lipoprotéine de cholestérol supérieure à 130 mg/dL ou basse densité lipoprotéine de cholestérol supérieure à 100 mg/dL (personnes avec maladie d’artère coronaire ou ses équivalents), ont été traités avec simvastatin ( n = 21) ou ezetimibe ( n = 23), 10 mg par jour. Dans tous les échantillons (avant et trois mois après le traitement), on a mesuré les niveaux de cholestérol total, triglycérides, grande densité lipoprotéine de cholestérol, basse densité lipoprotéine de cholestérol, apolipoprotéine A, apolipoprotéine B, lipoprotéine(a), homocystéine, facteur du tissu, von Willebrand et protéine C-réactive.
Résultats
Les prix premiers des lipides et des paramètres hématologiques ont été pareils dans les deux groupes. Simvastatin et ezetimibe ont diminué cholestérol total (262 à 189 mg/dL ; p < 0,001 et 268 à 220 mg/dL ; p = 0,001, respectivement), basse densité lipoprotéine de cholestérol (177 à 114 mg/dL ; p < 0,001 et 196 à 146 mg/dL ; p < 0,001, respectivement) et protéine C-réactive (1,15 à 0,3 mg/dL ; p = 0,001 et 2,8 à 0,8 mg/dL ; p = 0,005, respectivement). En plus, simvastatin a diminué apolipoprotéine B (125 à 93 mg/dL ; p < 0,001).
Conclusions
Les deux médicaments ont amélioré le profil lipidémique des malades et les niveaux de protéine C-réactive. Pourtant, aucune influence sur facteur du tissu ni sur von Willebrand n’a été trouvé.
Background
Simvastatin, like all other statins, is an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase – a key enzyme in the cholesterol-synthesis pathway. Statins have proven to be especially effective in reducing the concentration of low-density lipoprotein (LDL) cholesterol and, to a lesser extent, that of triglycerides . Furthermore, when administered in either primary or secondary prevention of coronary heart disease, statins reduce coronary morbidity and mortality effectively . Until recently, it was believed that the beneficial effects of statins were due solely to their lipid-lowering actions . Several studies have reported that besides their beneficial influence on lipid profiles, statins have additional, or pleiotropic , effects . These studies examined a variety of disorders, and showed various benefits, ranging from an improvement in bone mineral density to a reduction in the incidence of Alzheimer’s disease . Furthermore, the Scandinavian Simvastatin Survival Study and the Heart Protection Study demonstrated that simvastatin therapy improves endothelial function, which is a strong and an independent predictor of cardiovascular events .
Ezetimibe is an intestinal cholesterol absorption inhibitor. Actually, in contrast to statins, ezetimibe reduces feeding cholesterol concentration without any effect on the absorption of triglycerides, fat acids, cholic acids and fat-soluble vitamins . Concerning pleiotropic effects, ezetimibe therapy does not improve endothelium-dependent vasodilation, despite the reduction in LDL cholesterol serum concentration .
Tissue factor (TF), formerly known as thromboplastin, is a cell surface glycoprotein, synthesized and expressed by a wide variety of cells . Accumulating evidence presents TF as a multifaceted transmembrane signalling receptor involved in the regulation of angiogenesis, tumour growth, metastasis and inflammation . Elevated concentrations of TF are observed in patients with hypertension, diabetes mellitus or dyslipidaemia, in smokers, and in those with acute coronary syndromes .
Von Willebrand’s factor (vWf) is a protein that ensures prothrombotic factor VIII binding and transport, and regulates platelet adhesion (to the appropriate receptors), platelet accumulation and thrombus formation . Plasma vWf is increased in patients with major risk factors for atherosclerosis and in documented cardiovascular disease .
C-reactive protein (CRP) is a circulating inflammatory marker that promotes thrombosis and may also promote arterial and tissue damage by several mechanisms . CRP may contribute not only to the prognosis of coronary syndromes and acute stroke, but also to the prediction of cardiovascular events in the general population .
The objective of the present study was to assess the effect of simvastatin or ezetimibe therapy on the concentration of TF, vWf and CRP, after similar reductions in LDL cholesterol concentration by both drugs.
Methods
Subjects
Forty-four patients with mild hypercholesterolaemia (total cholesterol ≈ 265 mg/dL) were selected to ensure similar reductions in LDL cholesterol concentration after the administration of simvastatin or ezetimibe. All patients were from the Lipid Clinic of the Onassis Cardiac Surgery Centre, Athens, Greece. The centre’s Institutional Review Board approved the study. The diagnosis for mild hypercholesterolaemia was based on the following criteria: total cholesterol >240 mg/dL and LDL cholesterol >130 mg/dL; or LDL cholesterol >100 mg/dL in patients with coronary artery disease or its equivalent; or LDL cholesterol >70 mg/dL in patients with coronary artery disease and diabetes mellitus or metabolic syndrome or restenosis or multiple risk factors or who were smokers . Smokers were defined as current or ex-smokers; non-smokers were defined as those who had never smoked. Women were defined as postmenopausal when they reported their last menses to have been at least 12 months earlier; they were not on hormone replacement therapy. Heavy drinking, liver and renal disease, obesity and diabetes mellitus, hypothyroidism and professional sport activity were exclusion criteria.
The subjects were divided into two groups: 23 patients (11 men and 12 postmenopausal women) were treated with ezetimibe 10 mg daily while 21 patients (13 men and eight postmenopausal women) were treated with simvastatin 10 mg daily. Blood samples were drawn before and 3 months after the treatment. In both samples we measured the concentration of total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, apolipoprotein A, apolipoprotein B, lipoprotein(a), homocysteine, TF, vWf and CRP. Patients were selected randomly and were matched for age, sex, body mass index, lipid profile and haematological variables.
Determination of blood lipids
Plasma total cholesterol, triglycerides and HDL cholesterol concentrations were measured using enzymatic colorimetric methods on a Roche Integra Biochemical analyser, with commercially available kits (Roche Diagnostics Gmbh, Mannheim, Germany). Serum LDL cholesterol concentration was calculated using the Friedewald’s formula in patients with a triglyceride concentration <400 mg/dL. Apolipoprotein A, apolipoprotein B and lipoprotein(a) concentrations were measured by nephelometry (Nephelometer: BN-100, Behring, Germany). Blood glucose concentration was measured by the hexokinase method with a Dade Behring reagent on a Dimension instrument (Dade Behring, Liederbach, Germany). Homocysteine concentration was calculated using the Axsym Abbott method, vWf plasma concentration was defined by the congealed method and TF concentration by an enzyme-linked immunosorbent assay (ELIZA), and CRP concentration was measured by immunonephelometry.
Statistical analysis
Post-hoc power analysis showed that the differences found in total cholesterol in both subgroups and the sample size of the study produced a statistical power of 61.02% at a significance level of p < 0.05. Owing to the non-normal distribution of continuous variables, non-parametric statistics were used. The aforementioned variables are presented as medians and interquartile ranges, while categorical variables are shown as absolute and relative frequencies (percentages). In order to assess any differences at baseline or after 3 months, the Mann-Whitney statistic was used. Any differences in the distribution of continuous variables between the start and the end of the study were evaluated using the Wilcoxon sign-rank test for both treatment groups. The potential association between categorical variables and treatment was tested using Pearson’s Chi 2 statistic. In order to adjust for the inflation of type I error due to the large number of multiple comparisons, we used the Bonferroni correction, setting a new level of p -value, which was considered to be significant if <0.001 for each two-sided test. Data were analysed using STATA™ (Version 9.0, Stata Corporation, College Station, TX, USA).
Results
Baseline characteristics
The clinical and biochemical characteristics of the two groups are shown in Table 1 . As expected, given the study design, there were no significant differences between the two patient groups in terms of age, body mass index (calculated as weight divided by height squared and expressed in kg/m 2 ), waist circumference or baseline lipid and haematological variables. There were no significant differences between the two groups in terms of sex, number of smokers or frequency of diabetes mellitus or coronary heart disease.
| Ezetimibe ( n = 23) | Simvastatin ( n = 21) | p | |
|---|---|---|---|
| Age (years) | 57 ± 19 | 57 ± 17 | 0.86 |
| Height (cm) | 1.7 ± 0.2 | 1.7 ± 0.1 | 0.62 |
| Weight (kg) | 80 ± 21 | 82 ± 15.8 | 0.59 |
| Waist (cm) | 99 ± 15 | 98 ± 11.5 | 0.49 |
| Body mass index (kg/m 2 ) | 26.9 ± 5.7 | 28.1 ± 4.2 | 0.57 |
| Total cholesterol b (mg/dL) | 268 ± 38 | 262 ± 57 | 0.29 |
| Triglycerides b (mg/dL) | 138 ± 84 | 117 ± 75 | 0.79 |
| High-density lipoprotein b (mg/dL) | 52 ± 11 | 50 ± 17.6 | 0.81 |
| Low-density lipoprotein b (mg/dL) | 196 ± 43 | 177 ± 52.3 | 0.13 |
| Apolipoprotein A b (mg/dL) | 143 ± 41 | 145 ± 32 | 1.00 |
| Apolipoprotein B b (mg/dL) | 123 ± 29 | 125 ± 26.5 | 0.89 |
| Lipoprotein(a) b (mg/dL) | 16 ± 25.6 | 32 ± 56.5 | 0.32 |
| Glucose b (mg/dL) | 94 ± 24 | 98 ± 34.5 | 0.12 |
| Total cholesterol a (mg/dL) | 220 ± 38 | 189 ± 52 | 0.001 |
| Triglycerides a (mg/dL) | 108 ± 71 | 112 ± 37.5 | 1.00 |
| HDL cholesterol a (mg/dL) | 54 ± 12 | 52 ± 19 | 0.66 |
| LDL cholesterol a (mg/dL) | 146 ± 37 | 114 ± 36 | <0.001 |
| Apolipoprotein A a (mg/dL) | 142 ± 40 | 159 ± 26 | 0.43 |
| Apolipoprotein B a (mg/dL) | 108 ± 27 | 93 ± 28 | 0.04 |
| Lipoprotein(a) a (mg/dL) | 13 ± 34 | 20 ± 60.4 | 0.42 |
| Glucose a (mg/dL) | 98 ± 15 | 104 ± 30 | 0.12 |
| Systolic blood pressure (mmHg) | 128 ± 20 | 120 ± 18.5 | 0.99 |
| Homocysteine b (μmol/L) | 11.3 ± 5.7 | 10.5 ± 4.2 | 0.17 |
| von Willebrand’s factor b (μg/mL) | 120 ± 71 | 113 ± 36.5 | 0.93 |
| Tissue factor b (μg/mL) | 25.2 ± 25.2 | 23.2 ± 26.2 | 0.96 |
| C-reactive protein b (mg/L) | 2.8 ± 4.6 | 1.145 ± 3.0 | 0.26 |
| Homocysteine a (μmol/L) | 11 ± 4.2 | 10.6 ± 4.8 | 0.87 |
| von Willebrand’s factor a (μg/mL) | 126 ± 78 | 117 ± 43.5 | 0.97 |
| Tissue factor a (μg/mL) | 32.16 ± 30.5 | 22 ± 27.8 | 0.20 |
| C-reactive protein a (mg/L) | 0.8 ± 1.4 | 0.3 ± 2.2 | 0.23 |
| Diastolic blood pressure (mmHg) | 75 ± 10 | 80 ± 10 | 0.50 |
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